SUMMARY. Francesca Filbey has extensive research experience in neuropsychology and neuroimaging methods in the study of psychiatric and neurologic populations. Although she studied populations who are genetically at-risk for brain disorders, she has not been directly involved in the genetic aspects. Her immediate career goal is to acquire the research and professional skills necessary for achieving her long-term goal of developing an independent, extramurally funded translational research that spans genetics, cognitive and neuroimaging approaches to the study of substance abuse in humans. A five-year Career Development Plan will provide the candidate with the multi-disciplinary skills required to ultimately lead an independent and highly productive research program in substance abuse. Three specific aims are proposed to test the overall global hypothesis that CNR1 genotype increase one's risk to long-term and irreversible effects of substance abuse in the developing brain. We propose (1) to determine the functional significance of CNR1 genotype on brain function; (2) to identify and characterize the effects of marijuana use on brain function; and (3) to determine the compounding effects of these risk factors on the developing brain. We will test our global hypothesis by comparing brain function in adult sib-pairs (> 18 years old) who are (1) concordant for the polymorphism but discordant for adolescent cannabis use, (2) discordant for the polymorphism but concordant for adolescent cannabis use and (3) discordant for both CNR1 genotype and marijuana use. Brain function will be measured by functional magnetic resonance imaging (fMRI) while individuals are presented with tasks that elicit activity in the dopaminergic-reward pathway. This study will offer insight into the genetic determinants that increase one's vulnerability to the effects of substance abuse, in addition to the underlying neural mechanisms that lead to neural dysfunction related to substance abuse. RELEVANCE. The findings from these studies will demonstrate that the modulating effects of CNR1 genotype on the effects of substance abuse leads to enduring and deleterious effects. These findings will impact prevention and intervention strategies in the substance abusing population. These findings will also contribute to the understanding of the neurotransmitter pathways involved in substance abuse, thereby aiding in the development of more effective pharmacotherapies. [unreadable] [unreadable] [unreadable]